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Título:

Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically relevant concentrations

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Autor:

Yadav, Pramod Kumar
Vitvitsky, Victor
Carballal, Sebastián
Seravalli, Javier
Banerjee, Ruma

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Artículo

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Palabras clave:

Allosteric regulation
Enzyme kinetics
Hydrogen sulfide
Oxidation-reduction (redox)
Thioredoxin

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ANIMALES
CATÁLISIS
CÉLULAS HEK293
CÉLULAS HEP G2
HUMANOS
QUÍMICA
ISOENZIMAS
METABOLISMO
MASCULINO
RATONES
RATONES ENDOGÁMICOS BALB C
ESPECIFICIDAD DE ÓRGANOS
SULFURTRANSFERASAS
TIORREDOXINAS

Año de publicación:

2020

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Resumen:

3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser-His-Asp triad, proposed to serve a general acid-base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg-1 in brain to 1.4 μmol·kg-1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.

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American Society for Biochemistry and Molecular Biology

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Journal of Biological Chemistry. 2020;295(19):6299-6311

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Citación:

Yadav P, Vitvitsky V, Carballal S y otros. Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically relevant concentrations. Journal of Biological Chemistry [en línea]. 2020;295(19):6299-6311

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Licencia Creative Commons Atribución (CC - By 4.0)

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